Substituted 1,2,3,4-tetrahydrocyclopent b!indoles, compositions and use

ABSTRACT

There are disclosed various compounds of the formula below, ##STR1## where n, X and R 1  through R 4  are as defined in the specification, which are useful for alleviating various memory dysfunctions characterized by a cholinergic deficit such as Alzheimer&#39;s disease. 
     Compounds of this invention also inhibit monoamine oxidase and/or act at central α 2  -adrenergic receptors, and hence are useful as antidepressants.

This is a division of a prior application, Ser. No. 177,035, filed Jan.4, 1994, which is a divisional of a prior application Ser. No. 976,067,filed Nov. 13, 1992, now U.S. Pat. No. 5,298,626, which is a division ofa prior application, Ser. No. 818,703, filed Jan. 9, 1992, now U.S. Pat.No. 5,192,789, which is a continuation-in-part of a prior application,Ser. No. 642,952, filed Jan. 18, 1991, now U.S. Pat. No. 5,100,891.

The present invention relates to compounds of the formula, ##STR2##where n is 2, 3, 4 or 5;

X is hydrogen, loweralkyl, loweralkoxy, hydroxy, halogen,trifluoromethyl or nitro;

R₁ is hydrogen, loweralkyl, loweralkenyl, loweralkynyl, aminoloweralkyl,loweralkylaminoloweralkyl, diloweralkylaminoloweralkyl, cycloalkyl,cycloalkylloweralkyl, cycloalkenyl, aryl, arylloweralkyl,arylcycloalkyl, ##STR3## the group "ALK" signifying a divalentloweralkenyl group, and Y signifying hydrogen, loweralkyl, aryl orarylloweralkyl;

R₂ is hydrogen, loweralkyl, formyl, loweralkylcarbonyl,benzyloxycarbonyl or loweralkylaminocarbonyl; or alternatively, thegroup ##STR4## R₃ is hydrogen, loweralkyl, arylloweralkyl,loweralkylcarbonyl or loweralkoxycarbonyl;

R₄ is hydrogen, ##STR5## wherein R₅ is loweralkyl, loweralkenyl,loweralkynyl, cycloalkyl, cycloalkylloweralkyl, aryl, arylloweralkyl,arylcycloalkyl; and

R₆ is hydrogen, loweralkyl, aryl or arylloweralkyl;

or alternatively the group ##STR6## as a whole is ##STR7## R₇ isloweralkyl, aryl or arylloweralkyl; which compounds are useful foralleviating various memory dysfunctions characterized by a cholinergicdeficit such as Alzheimer's disease. Compounds I of this invention alsoinhibit monoamine oxidase and/or act at central α₂ -adrenergicreceptors, and hence are useful as antidepressants.

Also included within the scope of this invention are compounds ofFormula II, where R₃, R₄, X and n are as previously defined, which areuseful as direct precursors to the target compounds of this invention.

Also included within the scope of this invention are compounds ofFormula III, where R₈ is hydroxy, aminoloweralkoxy, loweralkyl,cycloalkyl, cycloalkenyl, arylloweralkyl, arylcycloalkyl,loweralkylcarbonyloxy or loweraminocarbonyloxy; which are useful foralleviating various memory dysfunctions characterized by a cholinergicdeficit such as Alzheimer's disease. Compounds III of this inventionalso inhibit monoamine oxidase and/or act as presynaptic α₂ -adrenergicreceptor antagonists, and hence are useful as antidepressants. ##STR8##

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and the appended claims.

The term loweralkyl shall mean a straight or branched alkyl group havingfrom 1 to 6 carbon atoms. Examples of said loweralkyl include methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl andstraight-and branched-chain pentyl and hexyl.

The term cycloalkyl shall mean a cycloalkyl group of 3 to 7 carbonatoms.

The term halogen shall mean fluorine, chlorine, bromine or iodine.

The term aryl shall mean a phenyl group substituted with 0, 1 or 2substituents, each of which being independently loweralkyl, loweralkoxy,halogen, trifluoromethyl, hydroxy or nitro.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and tautomeric isomers wheresuch isomers exist.

The compounds of this invention are prepared by utilizing one or more ofthe synthetic steps described below.

Throughout the description of the synthetic steps, the notations n, X, Yand R₁ through R₈ shall have the respective meanings given above unlessotherwise stated or indicated.

STEP A:

A compound of Formula IV, where R₉ is hydrogen or --OCH₃, is allowed tocyclize to afford a compound of Formula V. This reaction is typicallyconducted in aqueous sulfuric acid at a temperature of 25° to 150° C.##STR9## STEP B:

Compound V is allowed to react with a sulfate compound of the formula,(R₁₀ O)₂ SO₂, where R₁₀ is loweralkyl or arylloweralkyl, in a routinemanner known to the art to afford a compound of Formula VI.Alternatively, compound V is allowed to react with a halide compound ofthe formula R₁₀ -Hal, where R₁₀ is as defined above, in a routine mannerknown to the art, to afford a compound of Formula VI. ##STR10## STEP C:

Compound V is allowed to react with a diloweralkyl pyrocarbonate of theformula, R₁₁ --O--CO--O--CO--O--R₁₁ , where R₁₁ is a loweralkyl group,in the presence of a suitable catalyst, preferably4-dimethylaminopyridine, to afford a compound of Formula VII. ##STR11##STEP D:

Compound V is allowed to react with an acyl chloride of the formula R₁₁--CO--Cl in a routine manner known to the art to afford a compound ofFormula VIII. ##STR12## STEP E:

A compound of Formula IX obtained from STEP B is subjected to a cleavagereaction to afford a compound of Formula X. Typically, to this end,compound IX is allowed to react with BBr₃ /tetrahydrofuran complex andthe resultant product is hydrolyzed in a routine manner known to theart. ##STR13## STEP F:

As a special case, a compound of Formula XI is allowed to react withchloroacetyl chloride in the presence of aluminum chloride in a routinemanner known to the art to afford a compound of Formula XII(Friedel-Crafts reaction). ##STR14## STEP G:

Compound XII is allowed to react with a peracid, preferablym-chloroperbenzoic acid in a routine manner known to the art to afford acompound of Formula XIII (Baeyer-Villiger reaction). ##STR15## STEP H:

Compound XIII is hydrolyzed preferably in the presence of a base such assodium hydroxide to afford a compound of Formula XIV. ##STR16## STEP I:

A compound of Formula XV, where R₁₂ is hydrogen, methoxy or hydroxy,which is obtained from one of the foregoing steps is allowed to reactwith hydroxylamine hydrochloride in a routine manner known to the art toafford a compound of Formula XVI. Typically, this reaction is conductedby first suspending compound XV in ethanol and thereafter adding anaqueous solution of sodium acetate and an aqueous solution ofhydroxylamine hydrochloride to the suspension and stirring the resultantmixture at a temperature of 25° to 150° C. ##STR17## STEP J:

Compound XVI is allowed to react with an aminoloweralkyl bromide of theformula, Br--R₁₃ --NH₂, where--R₁₃ --NH₂ is an aminoloweralkyl group, ina routine manner known to the art to afford a compound of Formula XVII.##STR18## STEP K:

Compound XV is allowed to react with a primary amine of the formula##STR19## where R₁₄ is loweralkyl, loweralkenyl, loweralkynyl cycloalkylcycloalkenyl, arylloweralkyl, arylcycloalkyl or aryl, in a routinemanner known to the art to afford an imine of Formula XVIII.

It is preferable to conduct this reaction in the presence of titanium(IV) isopropoxide and a suitable solvent such as acetonitrile.Typically, this reaction is conducted at a temperature of 0° to 80° C.This method is more advantageous than a method using TiCl₄ or a methodwherein the reaction is conducted in a sealed tube at an elevatedtemperature with the aid of molecular sieves used as a water removingagent. ##STR20## STEP L:

Compound XVI is reduced with the aid of a Raney alloy and a sodiumhydroxide solution in a similar manner as reported by B. Staskun and T.van Es (J. Chem. Soc., C., 531 (1966)) to afford a compound of FormulaXIX. ##STR21## STEP M:

Compound XV is allowed to react with titanium isopropoxide and asecondary amine of the formula, ##STR22## where the group ##STR23## is##STR24## followed by reduction with sodium cyanoborohydride underconditions similar to that described by R. J. Mattson et al., J. Org.Chem., 55, 2552-4 (1990), to afford a compound of Formula XX. ##STR25##STEP N:

Compound XVIII is reduced with sodium borohydride, sodiumcyanoborohydride or borane/tetrahydrofuran complex in a routine mannerknown to the art to afford a compound of Formula XXI. ##STR26## STEP O:

Compound XIX is reduced with the aid of borane/tetrahydrofuran andtrifluoroacetic acid complex to afford a compound of Formula XXII.##STR27## STEP P:

A compound of Formula XXIII, which is obtained from STEP L or O, isallowed to react with a halide compound of the formula R₁₅ -Hal whereR₁₅ is loweralkyl, loweralkenyl, loweralkynyl, cycloalkylloweralkyl,arylloweralkyl, ##STR28## to afford a compound of Formula XXIV.##STR29## STEP Q:

A compound of Formula XXV, where R₁₆ is hydrogen, loweralkyl,loweralkenyl, loweralkynyl, cycloalkyl, cycloalkenyl, arylloweralkyl orarylcycloalkyl, is allowed to react with formic acid in the presence of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and4-dimethylaminopyridine or the mixed anhydride prepared from formic acidand acetic anhydride to afford a compound of Formula XXVI. ##STR30##STEP R:

Compound XXV is allowed to react with an acyl chloride of the formula,R₁₇ --CO--Cl, where R₁₇ is a loweralkyl group, in a routine manner knownto the art to afford a compound of Formula XXVII. ##STR31## STEP S:

A compound of Formula XXV, where R₁₂ is not hydroxy, is allowed to reactwith a benzyl chloroformate in a routine manner known to the art toafford a compound of Formula XXVIII. ##STR32## STEP T:

A compound of Formula XXV, where R₁₂ is not hydroxy, is allowed to reactwith an isocyanate of the formula R₁₇ --N═C═O, where R₁₇ is aloweralkyl, aryl or arylloweralkyl group, to afford a compound ofFormula XXIX. Typically, this reaction is conducted in the presence of asuitable catalyst such as 1,8-diazabicyclo 5.4.0 !undec-7-ene. ##STR33##STEP U:

A compound of Formula XVI, where R₁₂ is not hydroxy, is allowed to reactwith an isocyanate of the formula R₁₇ --N═C═O in substantially the samemanner as in STEP T to afford a compound of Formula XXX. ##STR34## STEPV:

Compound XVI is allowed to react with an acyl chloride of the formulaR₁₇ --CO--Cl or an acid anhydride of the formula (R₁₇ --CO)₂ O in aroutine manner known to the art to afford a compound of Formula XXXI.##STR35## STEP W:

A compound of Formula XXXII, where R₂ is not loweralkylaminocarbonyl,which is obtained from one of the foregoing STEPS is allowed to reactwith a chloroformate of the formula ##STR36## in a routine manner knownto the art to afford a compound of Formula XXXIII. ##STR37## STEP X:

A compound of Formula XXXIIIa which is obtained from STEP W is allowedto react with an isocyanate of the formula R₁₇ --N═C═O in substantiallythe same manner as in STEP T to afford a compound of Formula XXXIV.Subsequently, Compound XXXIV is subjected to hydrogenolysis conductedwith the aid of a suitable catalyst such as palladium-carbon in aroutine manner known to the art to afford a compound of Formula XXXV.##STR38## STEP Y:

A compound of Formula XXXVI, which is obtained from one of the foregoingSTEPS, is allowed to react with an isocyanate of the formula R₁₇ --N═C═Oin substantially the same manner as in STEP T to afford a compound ofFormula XXXVII. ##STR39##

The compounds of Formula I and Formula III of the present invention areuseful for the treatment of various memory dysfunctions characterized bya decreased cholinergic function such as Alzheimer's disease. Compoundsof this invention also inhibit monoamine oxidase and/or act at centralα₂ -adrenergic receptors and hence are useful as antidepressants.

The activity to alleviate such memory dysfunctions is manifested by theability of these compounds to inhibit the enzyme acetylcholinesteraseand thereby increase acetylcholine levels in the brain.

Cholinesterase Inhibition Assay

Cholinesterase are found throughout the body, both in the brain and inserum. However, only brain acetylcholinesterase (ACHE) distribution iscorrelated with central cholinergic innervation. This same innervationis suggested to be weakened in Alzheimer patients. We have determined invitro inhibition of acetylcholinesterase activity in rat striatum.

In Vitro Inhibition of Acetylcholinesterase Activity in Rat Striatum

Acetylcholinesterase (AChE), which is sometimes called true or specificcholinesterase, is found in nerve cells, skeletal muscle, smooth muscle,various glands and red blood cells. AChE may be distinguished from othercholinesterases by substrate and inhibitor specificities and by regionaldistribution. Its distribution in brain roughly correlates withcholinergic innervation and subfractionation shows the highest level innerve terminals.

It is generally accepted that the physiological role of AChE is therapid hydrolysis and inactivation of acetylcholine. Inhibitors of AChEshow marked cholinomimetic effects in cholinergically-innervatedeffector organs and have been used therapeutically in the treatment ofglaucoma, myasthenia gravis and paralytic ileus. However, recent studieshave suggested that AChE inhibitors may also be beneficial in thetreatment of Alzheimer's disease.

The method described below was used in this invention for assayingcholinesterase activity. This is a modification of the method of Ellmanet al., Biochem. Pharmacol. 7, 88 (1961).

Procedure:

A. Reagents

1. 0.05M Phosphatic buffer, pH 7.2

(a) 6.85 g NaH₂ PO₄.H₂ O/100 ml distilled H₂ O

(b) 13.40 g Na₂ HPO₄.7H₂ O/100 ml distilled H₂ O

(c) add (a) to (b) until pit reaches 7.2

(d) Dilute 1:10

2. Substrate in buffer

(a) 198 mg acetylthiocholine chloride (10 mM)

(b) q.s. to 100 ml with 0.05M phosphate buffer, pH 7.2 (reagent 1)

3. DTNB in buffer

(a) 19.8 mg 5,5-dithiobisnitrobenzoic acid (DTNB) (0.5 mM)

(b) q.s. to 100 ml with 0.05M phosphate buffer, pH 7.2 (reagent 1)

4. A 2 mM stock solution of the test drug is made up in a suitablesolvent and q.s. to volume with 0.5 mM DTNB (reagent 3). Drugs areserially diluted (1:10) such that the final concentration (in cuvette)is 10⁻⁴ M and screened for activity. If active, IC₅₀ values aredetermined from the inhibitory activity of subsequent concentrations.

B. Tissue Preparation

Male Wistar rats are decapitated, brains rapidly removed, corporastriata dissected free, weighed and homogenized in 19 volumes(approximately 7 mg protein/ml) of 0.05M phosphate buffer, pH 7.2 usinga Potter-Elvehjem homogenizer. A 25 microliter aliquot of the homogenateis added to 1.0 millliter vehicle or various concentrations of the testdrug and preincubated for 10 minutes at 37° C.

C. Assay

Enzyme activity is measured with the Beckman DU-50 spectrophotometer.This method can be used for IC₅₀ determinations and for measuringkinetic constants.

Instrument Settings

Kinetics Soft-Pac Module #598273 (10)

Program #6 Kindata:

Source--Vis

Wavelength--412 nm

Sipper--none

Cuvettes--2 ml cuvettes using auto 6-sampler

Blank--1 for each substrate concentration

Interval time--15 seconds (15 or 30 seconds for kinetics)

Total time--5 minutes (5 or 10 minutes for kinetics)

Plot--yes

Span--autoscale

Slope--increasing

Results--yes (gives slope)

Factor--1

Reagents are added to the blank and sample cuvettes as follows:

Blank: 0.8 ml Phosphate Buffer/DTNB

0.8 ml Buffer/Substrate

Control: 0.8 ml Phosphate Buffer/DTNB/Enzyme

0.8 ml Phosphate Buffer/Substrate

Drug: 0.8 ml Phosphate Buffer/DTNB/Drug/Enzyme

0.8 ml Phosphate Buffer/Substrate

Blank values are determined for each run to control for non-enzymatichydrolysis of substrate and these values are automatically subtracted bythe kindata program available on kinetics soft-pac module. This programalso calculates the rate of absorbance change for each cuvette.

For IC₅₀ Determinations:

Substrate concentration is 10 mM diluted 1:2 in assay yielding finalconcentration of 5 mM. DTNB concentration is 0.5 mM yielding 0.25 mMfinal concentration. ##EQU1## IC₅₀ values are calculated from log-probitanalysis

Results of this assay for some of the compounds of this invention andphysostigmine (reference compound) are presented in Table 1.

                  TABLE 1    ______________________________________                       Inhibitory Concentration,                       IC.sub.50 (μM)    Compound           Brain AChE    ______________________________________    3-(N-cyclopropyl)amino-4-methyl-                       3.5    1,2,3,4-tetrahydrocyclopent b!-    indol-7-yl methylcarbamate    4-methyl-3-phenylmethylamino-                       1.1    1,2,3,4-tetrahydrocyclopent b!-    indol-7-yl methylcarbamate    4-methyl-3-phenylmethylimino-                       6.2    1,2,3,4-tetrahydrocyclopent b!-    indol-7-yl methylcarbamate    Physostigmine      0.006    ______________________________________

This utility is further demonstrated by the ability of these compoundsto restore cholinergically deficient memory in the Dark Avoidance Assaydescribed below.

Dark Avoidance Assay

In this assay mice are tested for their ability to remember anunpleasant stimulus for a period of 24 hours. A mouse is placed in achamber that contains a dark compartment; a strong incandescent lightdrives it to the dark compartment, where an electric shock isadministered through metal plates on the floor. The animal is removedfrom the testing apparatus and tested again, 24 hours later, for theability to remember the electric shock.

If scopolamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animal's initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment.

Results of this assay for some of the compounds of this invention andthose for tacrine and pilocarpine (reference compounds) are presented inTable 2.

                  TABLE 2    ______________________________________                Dose        % of Animals with                (mg/kg of body                            Scopolamine Induced    Compound    weight, s.c.)                            Memory Deficit Reversal    ______________________________________    3-(N-cyclopropyl)-                0.63        27%    amino-4-methyl-                2.5         33%    1,2,3,4-tetrahydro-    cyclopent b!indol-    7-yl methyl-    carbamate    Tacrine     0.63        13%    Pilocarpine 5.0         13%    ______________________________________

The utility is further demonstrated by the ability of these compounds toinhibit the enzyme monoamine oxidase, increase the brain levels ofbiogenic amine(s), and act as antidepressants.

Inhibition of Type A and Type B Monoamine Oxidase Activity in Rat BrainSynaptosomes

Purpose

To determine the selective inhibition of the two forms of monoamineoxidase (MAO).

Introduction

The metabolic deamination of amines has been known for over a hundredyears, but more recently Johnston (1) described two forms of monoamineoxidase, which are called "type A" and "type B". The existence of thetwo forms is based on different substrate and inhibitor specificities.Serotonin (5HT) and norepinephrine (NE) are substrates for type A MAO,β-phenethylamine (PEA) and benzylamine are substrates for type B MAO,while dopamine (DA) and tyramine are substrates for both types.Clorgyline is a selective inhibitor of the type A enzyme, deprenyl andpargyline are selective inhibitors of the type B enzyme andtranylcypromine and iproniazid are nonselective inhibitors (2). It isrecognized that MAO inhibitors have antidepressant properties. Althoughvarious methods for measuring MAO activity are available, the describedmethod involves the extraction of the radiolabeled deaminatedmetabolites of ³ H!-5HT or ¹⁴ C!-β-phenethylamine. This procedure allowsMAO-A and MAO-B activities to be measured either simultaneously orindividually (3).

Procedure

A. Reagents

1. Phosphate buffer (0.5M), pH 7.4: 134.4 g NaH₂ PO₄.7H₂ O q.s. to 1liter in distilled H₂ O (A) 17.3 g Na₂ HPO₄ q.s. to 250 ml in distilledH₂ O (B) Adjust pH of A to 7.4 by slowly adding B (volumes as needed)Dilute 1:10 in distilled H₂ O (0.05M PO₄ buffer, pH 7.4)

2. 0.25M Sucrose (PO₄ buffered): 21.4 g sucrose, q.s. to 250 ml with0.05M PO₄ buffer

3. Substrate for MAO-A:

a. Serotonin creatine SO₄ (5HT) is obtained from Sigma Chemical Company.A 5 mM stock solution is made up in 0.01 N HCl. This is used to dilutethe specific activity of the ³ H!-5HT.

b. ³ H!-5-Hydroxytryptamine binoxalate (20-30 Ci/mmol) is obtained fromNew England Nuclear.

c. Add 12 μl of ³ H!-5HT to 2 ml of the 5 mM 5HT solution. (Final amineconcentration in the assay is 200 μM: see below.)

4. Substrate for MAO-B

a. β-phenethylamine (PEA) is obtained from Sigma Chemical Company. A 5mM stock solution is made up in 0.01 N HCl. This is used to dilute thespecific activity of the ¹⁴ C!-PEA.

b. β- ethyl-1-¹⁴ C!-phenethylamine hydrochloride (40-50 mCi/mmol) isobtained from New England Nuclear.

c. Add 12 μl of ¹⁴ C!-PEA to 2 ml of the 5 mM PEA solution. (Final amineconcentration in the assay is 200 μM: see below.)

5. Equal amounts of MAO-A (SHT) and MAO-B (PEA) substrates are combinedfor simultaneously testing both MAO types, i.e. mixed stock solution of2.5 mM 5HT and 2.5 mM PEA, 40 μl of this mixed solution gives a 200 μMfinal concentration of each amine in the assay. When testing only oneMAO type, the individual 5 mM stock solutions must be diluted 1:1 withdistilled water prior to adding 40 μl to the incubation mixture; i.e.,same 200 μM final amine concentration.

B. Tissue Preparation

Male Wistar rats weighting 15-250 grams were sacrificed and the brainsrapidly removed. Whole brain minus cerebellum was homogenized in 30volumes of ice-cold, phosphate-buffered 0.25M sucrose, using aPotter-Elvejhem homogenizer. The homogenate was centrifuged at 1000 gfor 10 minutes and the supernatant (S₁) decanted and recentrifuged at18,000 g for 20 minutes. The resulting pellet (P₂) was resuspended infresh 0.25M sucrose and served as the tissue source for mitochondrialMAO.

C. Assay

10 μl 0.5M PO₄ buffer, pH 7.4

50 μl H₂ O or appropriate drug concentration

400 μl Tissue suspension

Tubes are preincubated for 15 minutes at 37° C. and the assay is startedby adding 40 μl of combined substrate ( ³ H!-5HT and ¹⁴ C!-PEA) at 15second intervals. The tubes are incubated for 30 minutes at 37° C. andthe reaction stopped by the addition of 0.3 ml 2N HCl. Tissue blankvalues are determined by adding the acid before the radioactivesubstrate. The oxidative products of the reaction are extracted withethyl acetate/toluene (1:1). 5 ml of this mixture is added to the tubes,The resultant mixture is vortexed for 15 seconds to extract thedeaminated metabolites into the organic phase and the latter is allowedto separate from the aqueous phase. The tubes are placed in acetone/dryice bath to freeze the aquous layer. When this layer is frozen, the toporganic layer is poured into a scintillation vial. ¹⁰ ml of Liquiscintis added and the samples are counted using window settings for 14C inone channel and ³ H in the second channel. IC₅₀ values are determined bylog-probit analysis.

References

1. Johnston, J. P.: Some observations upon a new inhibitor of monoamineoxidase in brain tissue. Biochem. Pharmacol. 17:1285-1297 (1968).

2. Fowler, C. J. and Ross, S. B.: Selective inhibitors of monoamineoxidase A and B: biochemical, pharmacological and clinical properties.Med. Res. Rev. 4:323-328 (1984).

3. Kindt, M. V., Youngster, S. K., Sonsalla, P. K., Duvoisin, R. C. andHeikkila, R. E.: Role of monoamine oxidase-A (MAO-A) in thebioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTPanalog, 2'Me-MPTP. Eur. J. Pharmacol. 46:313:-318 (1988).

Results of the monoamine oxidase inhibition assay for representativecompounds of this invention are presented in Table 3.

                  TABLE 3    ______________________________________                     Inhibitory Concentration-                     IC.sub.50 (μM)    Compound           MAO-A     MAO-B    ______________________________________    1,2,3,4-Tetrahydro-                       0.29      0.32    cyclopent b!indol-3-    (2-propynyl)amine    3-(N-cyclopropyl)amino-                       0.32      0.42    4-methyl-1,2,3,4-    tetrahydrocyclopent b!-    indol-7-yl methylcarbamate    4-Methyl-3 (2-phenyl-                       15.2      3.7    cyclopropyl)imino!-1,2,3,4-    tetrahydrocyclopent b!indol-    7-yl methylcarbamate    (Reference Compounds)    Deprenyl           0.14      0.016    Tranylcypromine    0.19      0.12    ______________________________________

The present inventors have also conducted Clonidine Binding Assaydescribed below in order to ascertain the interaction of the compoundsof this invention with α₂ -receptors.

³ H-Clonidine Binding: α₂ -Receptor

Introduction:

A number of antidepressants have been shown to enhance neuronal releaseof norepinephrine by a presumed presynaptic α₂ -receptor blockade andthis property may be of significance with respect to the mechanism ofaction of these compounds. See references 1, 2 and 3 cited below. Theinteraction of a compound with central α₂ -receptors is assessed in the³ H-clonidine binding assay.

Procedure

A. Reagents

1. a. 57.2 g Tris HCl 16.2 g Tris Base -q.s. to 1 liter (0.5M Trisbuffer, pH 7.7)

b. Make a 1:10 dilution in distilled H₂ O (0.05M Tris buffer, pH 7.7)

2. Tris buffer containing physiological ions

a. Stock Buffer

NaCl 7.014 g

KCl 0.372 g

CaCl₂ 0.222 g-q.s. to 100 ml in 0.5M Tris buffer

MgCl₂ 0.204 g

b. Dilute 1:10 in distilled H₂ O. This yields 0.05M Tris HCl, pH 7.7;containing NaCl (120 mM), KCl (5 mM), CaCl₂ (2 mM) and MgCl₂ (1 mM)

3. 4-³ H!-Clonidine hydrochloride (20-30 Ci/mmol) is obtained from NewEngland Nuclear. For IC₅₀ determinations: ³ H-Clonidine is made up to aconcentration of 120 nM and 50 μl added to each tube (yields a finalconcentration of 3 nM in the 2 ml volume assay).

4. Clonidine-HCl is obtained from Boehringer Ingelheim. A stock solutionof 0.1 mM clonidine is made up to determine nonspecific binding. Thisyields a final concentration of 1 μM in the assay (20 μl to 2 ml).

5. Test compounds. For most assays, a 1 mM stock solution is made up ina suitable solvent and serially diluted, such that the finalconcentration in the assay ranges from 10⁻⁵ to 10⁻⁸ M. Sevenconcentrations are used for each assay and higher or lowerconcentrations may be used, depending on the potency of the drug.

B. Tissue Preparation

Male Wistar rats are sacrificed by decapitation and the conical tissuerapidly dissected. The tissue is homogenized in 50 volumes of 0.05M Trisbuffer, pH 7.7 (buffer 1b) with the Brinkman Polytron, then centrifugedat 40,000 g for 15 minutes. The supernatant is discarded and the pelletre-homogenized in the original volume of 0.05M Tris buffer, pH 7.7 andre-centrifuged as before. The supernate is discarded and the finalpellet re-homogenized in 50 volumes of buffer 2b. This tissue suspensionis then stored on ice. The final tissue concentration is 10 mg/ml.Specific binding is 1% of the total added ligand and 80% of total boundligand.

C. Assay

100 μl 0.5M Tris-physiological salts, pH 7.7 (buffer 2a)

830 μl H₂ O

20 μl Vehicle (for total binding)or 0.1 mM clonidine (for nonspecificbinding) or appropriate drug concentration

50 μl ³ H-clonidine stock

1000 μl tissue suspension

Tissue homogenates are incubated for 20 minutes at 25° C. with 3 nM ³H-clonidine and varying drug concentrations, and thereafter immediatelyfiltered under reduced pressure on Whatman GF/B filters. The filters arewashed with three five ml volumes of ice-cold 0.05M Tris buffer, pH 7.7,and thereafter transferred to scintillation vials. Ten ml of Liquiscintcounting solution is added to each sample which is then counted byliquid scintillation spectroscopy. Specific clonidine binding is definedas the difference between total bound and that performed usinglog-probit analysis. The percent inhibition at each drug concentrationis the mean of triplicate determinations.

References

1. P. F. VonVoigtlander, "Antidepressant and Antipsychotic Agents", in"Annual Reports in Medicinal Chemistry", F. H. Clarke, ed., Chapter 1,Academic Press, New York, N.Y. (1976);

2. S. Clements-Jewery, Neuropharmacol., 17,779 (1978);

3. C. B. Smith and P. J. Hollingsworth, "Adrenergic Receptors and theMechanism of Action of Antidepressant Treatments" in "Biochemical andPharmacological Aspects of Depression", K. F. Tipton and M. B. H.Youdim, eds., Taylor and Francis, New York, N.Y., Chapter 4 (1989).

Results of the ³ H-Clonidine Binding Assay for representative compoundsof this invention are presented in Table 4.

                  TABLE 4    ______________________________________    .sup.3 H-Clonidine Binding    Compound              IC.sub.50 (μM)    ______________________________________    1,2,3,3a,4,8b-Hexahydro-                          1.27    cyclopent b!indol-3-amine    2-naphthalenesulfonate hemihydrate    4-Methyl-1,2,3,4-tetrahydro-                          1.49    cyclopent b!indol-3-amine    4-Methyl-3-phenylmethylimino-                          0.85    1,2,3,4-tetrahydrocyclopent-     b!indol-7-ol    (Reference Compound)  3.9    Amitriptyline    ______________________________________

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsule or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric 2-naphthalenesulfonic and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweeting agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present inventions are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in disposable syringes or multiple dose vials made ofglass or plastic.

Examples of the compounds of this invention include:

1,2,3,4-tetrahydrocyclopen b!indol-3-amine;

4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-3-amine;

1,2,3,4-tetrahydrocyclopent b!indol-3-cyclopropylamine;

4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-3-cyclopropylamine;

1,2,3,4-tetrahydrocyclopent b!indol-3-(2-propynyl)amine;

1,2,3,4-tetrahydrocyclopent b!indol-3-(N-formyl)amine;

1,2,3,4-tetrahydrocyclopent b!indol-3-(N-phenylmethoxycarbonyl)amine;

1,2,3,3a,4,8b-hexahydrocyclopent b!indol-3-amine;

1,2,3,3a,4,8b-hexahydro-4-methylcyclopent b!indol-3-amine;

1,2,3,3a,4,8b-hexahydro-4-methylcyclopent b!indol-3-(2-propynyl)amine;

4-methyl-3-phenylmethylamino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol;

4-methyl-3-phenylmethylamino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate;

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!-indol-7-ol;

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent-bb!indol-7-yl methylcarbamate;

3-(N-cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-ol;

3-(N-cyclopropyl)amino-1,2,3,3a,4,8b-hexahydrocyclopent b!indol-7-ylphenylmethylcarbonate;

3-(N-cyclopropyl-N-methylaminocarbonyl)amino-1,2,3,3a,4,8b-hexahydrocyclopentb!indol-7-yl phenylmethylcarbonate;

3-(N-cyclopropyl-N-methylaminocarbonyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-ol;

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!-indol-7-yl methylcarbamate;

1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethylaminocyclopent-b!indol-7-ol

1,2,3,3a,4,8b-hexahydro-4-methyl-3-aminocyclopent b!indol-7-ol;

1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethoxycarbonylaminocyclopent b!indol-7-ol;

1,2,3,3a,4,8b-hexahydro-4-methyl-3-(N-phenylmethoxycarbonyl)aminocyclopentb!indol-7-ylmethylcarbamate;

1,2,3,3a,4,8b-hexahydro-4-methyl-3-methylaminocarbonylaminocyclopentb!indol-7-ol;

1,2,3,3a,4,8b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminocarbonyl)aminocyclopentb!indol-7-ol;

4-t-butyloxycarbonyl-1,4-dihydrocyclopent b!indol-3(2H)-one;

7-chloroacetyl-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one

7-chloroacetyloxy-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one;

1,4-dihydro-7-hydroxy-4-methylcyclopent b!indol-3(2H)-one;

1,4-dihydro-7-methylaminocarbonyloxy-4-methylcyclopentb!indol-(3(2H)-one

3-hydroxyimino-7-methoxy-1,2,3,4-tetrahydrocyclopent b!indole;

3-hydroxyimino-1,2,3,4-tetrahydrocyclopent b!indole;

3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indole;

3-(2-aminoethyl)oximino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indole;

3-cyclopropylamino-1,2,3,4-tetrahydrocyclopent b!indole;

3-cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indole;

3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol;

3-acetyloxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ylacetate;

4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol;

4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate;

4-methyl-3- (2-phenylcyclopropyl)imino!-1,2,3,4-tetrahydrocyclopent-b!indol-7-ol;

4-methyl-3- (2-phenylcyclopropyl)imino!-1,2,3,4-tetrahydrocyclopent-b!indol-7-yl methylcarbamate;

3-cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol;

3-methylaminocarbonyloximino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate;

3-(N-cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!-indol-7-yl methylcarbamate;

3-amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent b!indol-7-yl1,2,3,4-tetrahydroisoquinolylcarbamate;

5-bromo-3-(N-cyclopentyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-yl phenylmethylcarbamate;

3- 2-morpholinoethylamino!-4-methyl-1,2,3,4-tetrahydrocyclopentb!-indol-7-yl phenylethylcarbamate; and

4-methyl-3-(4-piperidinyl )amino-1,2,3,4-tetrahydrocyclopentb!indol-7-yl phenylethylcarbamate.

EXAMPLE 1 3Hydroxyamino-7-methoxy-1,2,3,4-tetrahydrocyclopent b!indole

A stirred solution of 1,2-cyclopentadione mono-4-methoxyphenylhydrazone(6.0 g) in 100 ml of 10% aqueous H₂ SO₄ was heated on a steam bath for 4hours and thereafter allowed to cool to room temperature and filtered togive 1,4-dihydro 7-methoxycyclopent b!indol-3(2H)-one as a solid. To theindole (2.6 g) in 25 ml of 95% EtOH was added hydroxylaminehydrochloride (1.7 g) in 15 ml water followed by sodium acetate (2.1 g)in 15 ml water. The mixture was heated at reflux for 2.5 hours andallowed to stand overnight. The EtOH was removed in vacuo and the solidmaterial which formed was collected and purified by flash chromatographyto give 0.8 g of a mixture of oxime isomers.

ANALYSIS: Calculated for C₁₂ H₁₂ N₂ O₂ : 66.65%C 5.59%H 12.95%N Found:66.39%C 5.51%H 12.91%N

EXAMPLE 2 3Hydroxyamino-1,2,3,4-tetrahydrocyclopent b!indole

To a stirred solution of 1,4-dihydrocyclopent b!indol-3(2H)-one Elks etal., J. Chem. Soc., 624 (1944). (10 g) in 100 ml of 95% EtOH was addedhydroxylamine hydrochloride (8.3 g) in 20 ml water followed by sodiumacetate (9.7 g) in 20 ml water. The mixture was heated at reflux for 2hours and thereafter allowed to stand at room temperature overnight. TheEtOH was removed in vacuo and the solid material which formed wascollected and recrystallized from 95% EtOH to give 4.5 g ofpredominantly one oxime isomer in the first crop and 3.0 g of a mixtureof oxime isomers from the second crop. A 1.5 g sample of the singleisomer was recrystallized to provide 0.9 g of analytically purematerial.

ANALYSIS: Calculated for C₁₁ H₁₀ N₂ O: 70.95%C 5.41%H 15.04%N Found:70.71%C 5.32%H 14.94%N

EXAMPLE 3 3Hydroxyamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indole

To a stirred solution of 1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one(3.0 g) in 30 ml of 95% EtOH was added hydroxylamine hydrochloride (2.25g) in 9 ml water followed by sodium acetate (4.4 g) in 9 ml water. Themixture was heated at reflux for 4 hours and thereafter an additional1.1 gram of hydroxylamine hydrochloride in 5 ml water and 2.2 grams ofsodium acetate in 5 ml water were added. After an additional 2 hours ofreflux, the mixture was allowed to stand at room temperature overnight.The material which precipitated was collected and recrystallized from95% EtOH to give 1.9 grams of analytically pure material.

ANALYSIS: Calculated for C₁₂ H₁₂ N₂ O: 71.98%C 6.04%H 13.99%N Found:72.18%C 6.11%H 14.00%N

EXAMPLE 4 3-(2-Aminoethyl)oximino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indole

To a stirred suspension of3-hydroxyamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indole (5.0 g) inmethylene chloride (50 ml) was added 50% NaOH (50 ml) followed bytetrabutylammonium bromide (800 mg) and bromoethylamine hydrobromide(7.6 g). The reaction mixture was stirred overnight at room temperature.The layers were separated and the aqueous layer was extracted withmethylene chloride (50 ml). The organic layers were combined, dried (Na₂SO₄) and concentrated. The product was purified via flash chromatographyon silica gel eluting with 10% methanol/methylene chloride to provide1.1 grams of purified material.

EXAMPLE 5 1,2,3,4-Tetrahydrocyclopent b!indol-3-amine

To a stirred solution of 3-hydroxyamino-1,2,3,4-tetrahydrocyclopentb!indole (6 g) in 150 ml of 95% EtOH at 0° C. was added a nickel alloy(Harshaw, Ni-1000P, 10 g) followed by 12.9 grams of sodium hydroxide in150 ml water. The ice bath was removed after 0.5 hour and the mixturewas stirred an additional hour and filtered. The EtOH was removed invacuo and the product crystallized to provide 5.0 grams of solid. Asample was recrystallized from toluene to provide analytically purematerial.

ANALYSIS: Calculated for C₁₁ H₁₂ N₂ : 76.71%C 7.02%H 16.26%N Found:76.44%C 6.98%H 15.99%N

EXAMPLE6 4-Methyl-1,2,3,4-tetrahydrocyclopent b!indol-3-aminehydrochloride

To a stirred solution of3-hydroxyamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indole (5 g) in200 ml 95% EtOH at 0° C. was added a nickel alloy (9 g) followed by 11grams of sodium hydroxide in 200 ml water. The ice bath was removedafter 0.25 hours and the mixture was stirred an additional hour.Additional nickel alloy (2×1 gram) was added and the mixture was stirredfor 2 hours. The catalyst was removed by filtration, the EtOH wasremoved in vacuo and the product extracted into CH₂ Cl₂ (2×100 ml). TheCH ₂ Cl₂ extracts were dried (Na₂ SO₄) and concentrated to give an oil(4.5 g). The oil (2.0 g) was dissolved in diethyl ether (100 ml) andethereal HCl was added until the solution became slightly acidic. Thesolid which formed was filtered and dried overnight to provide 1.6 gramsof 4-methyl-1,2,3,4-tetrahydrocyclopent b!indole-3-amine hydrochloride.

ANALYSIS: Calculated for C₁₂ H₁₄ N₂.HCl: 64.72%C 6.79%H 12.58%N Found:64.41%C 6.82%H 12.18%N

EXAMPLE 7 4-t-Butyloxycarbonyl-1,4-dihydrocyclopent b!indol-3(2H)-one

To a stirred solution of 1,4-dihydrocyclopent b!indol-3(2H)-one (10.0 g)in acetonitrile (100 ml) was added di-t-butylpyrocarbonate (15 g),followed by 4-dimethylaminopyridine (700 mg). The mixture was stirredovernight at room temperature under nitrogen. The solvent was removedunder reduced pressure and the residue was purified by flash columnchromatography to provide 4-t-butyloxy-carbonyl-1,4-dihydrocyclopentb!indole-3(2H)-one (4.5 g) as a solid.

ANALYSIS: Calculated for C₁₆ H₁₇ NO₃ : 70.83%N 6.32%H 5.16%N Found:71.04%C 6.35%H 5.16%N

EXAMPLE 8 1,2,3,4-tetrahydrocyclopent b!indol-3-cyclopropylaminehydrochloride

1,4-dihydrocyclopent b!indol-3(2H)-one (5.0 g) was separated into twoportions and placed into sealed tubes each containing toluene (20 ml),cyclopropylamine (2.0 ml) and 3 A molecular sieves (1 g). The mixtureswere placed in an oil bath and refluxed for 7 hours. Each tube wasallowed to cool to ambient temperature, the molecular sieves werefiltered, and the filtrate concentrated to give a brown solid which wasidentified as the imine via NMR/MS. The combined imine product wasdissolved in isopropanol (125 ml) and methanol (25 ml), and thereaftersodium borohydride (2.66 g) was added and the mixture was stirred undernitrogen at ambient temperature overnight. The mixture was cooled to 0°C., water was slowly added and the mixture was stirred 0.5 hours. Themixture was extracted with EtOAc (2×200 ml), the EtOAc layer wasextracted with 10% HCl (2×200 ml) and the acid extracts were neutralized(10% NaOH) and extracted with EtOAc (3×200 ml). The EtOAc extracts weredried (Na₂ SO₄) and concentrated in vacuo to give 3.5 grams of product.A 1.5 gram sample was dissolved in Et₂ O (100 ml) and ethereal HCl wasadded, the precipitate was collected and dried to provide1,2,3,4-tetrahydrocyclopent b!indol-3-cyclopropylamine hydrochloride.

ANALYSIS: Calculated for C₁₄ H₁₆ N₂.HCl 67.60%C 6.89%H 11.26%N Found:67.22%C 6.87%H 10.79%N

EXAMPLE 9 4-Methyl-1,2,3,4-tetrahydrocyclopentb!indol-3-cyclopropylamine 2-naphthalene sulfonate

1,4-Dihydro-4-methylcyclopent b!indol-3(2H)-one (2.0 g) andcyclopropylamine (3.0 g) were dissolved in 30 ml toluene and cooled to-10° C. Titanium tetrachloride (0.70 ml) was dissolved in 10 ml tolueneand added to the first solution. The reaction mixture was allowed towarm to room temperature and stirred overnight. The imine was isolatedby filtering the mixture through a pad of silica and removing thesolvent in vacuo. The imine (2.4 g) was dissolved in 100 ml of 5:1iPrOH/MeOH and thereafter sodium borohydride (1.2 g) was added. Thereaction mixture was stirred overnight. The solvents were removed andthe product purified by chromatography isolating the product as a yellowoil (1.6 g).

A 0.75 g portion of the cyclopropylaminoindole compound was dissolved in75 ml Et₂ O and stirred while a solution of 0.69 g of 2-naphthalenesulfonic acid in 50 ml Et₂ O was added slowly. A white precipitateformed which was filtered under N₂, washed with 2×50 ml Et₂ O and driedto afford 1.04 g of 4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-3-cyclopropylamine 2-naphthalene sulfonate.

ANALYSIS: Calculated for C₁₅ H₁₈ N₂.C₁₀ H₈ SO₃ : 69.10%C 6.03%H 6.45%NFound: 68.98%C 6.04%H 6.39%N

EXAMPLE 10 1,2,3,4-Tetrahydrocyclopent b!indol-3-(2-propynyl)amine

To a stirred solution of 1,2,3,4-tetrahydrocyclopent b!indol-3-amine(5.0 g) in tetrahydrofuran (30 ml) under nitrogen was addedtriethylamine (2.9 g) followed by a dropwise addition of propargylbromide (4.45 g, 80% solution in toluene) dissolved in tetrahydrofuran(20 ml). The mixture was stirred overnight. Additional propargyl bromide(0.01 mole) dissolved in tetrahydrofuran (10 ml) was added and themixture was stirred for 3 hours. The mixture was concentrated in vacuo,CH₂ Cl₂ (150 ml) was added and the mixture was extracted with 10% HCl(2x 50 ml). The organic phase was dried (Na₂ SO₄) and concentrated togive 0.85 gram of product. The reaction was repeated on the same scaleusing identical conditions. The products were combined andchromatographed on silica gel eluting with 5% MeOH/CH₂ Cl₂ to provide1,2,3,4-tetrahydrocyclopent b!indol- 3-(2-propynyl)amine (1.6 g).

ANALYSIS: Calculated for C₁₄ H₁₄ N₂ : 79.97%C 6.71%H 13.32%N Found:79.70%C 6.77%H 13.14%N

EXAMPLE 11 1,2,3,4-Tetrahydrocyclopent b!indol-3-(N-formyl)amine

To a stirred solution of 1,2,3,4-tetrahydrocyclopent b!indol-3-amine(2.0 g) in 25 ml methylene chloride at room temperature was added4-dimethylaminopyridine (1.4 g) followed by 0.46 ml of formic acid.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.24 g) wasadded and the mixture was stirred overnight under a nitrogen atmosphere.The reaction mixture was diluted with CH₂ Cl₂ (100 ml), extracted withwater (3×50 ml), dried (Na₂ SO₄) and concentrated in vacuo to give asolid which was crystallized from EtOH and recrystallized from tolueneto provide 1,2,3,4-tetrahydrocyclopent b!indol-3-(N-formyl)amine (1.1g).

ANALYSIS: Calculated for C₁₂ H₁₂ N₂ O: 71.98%C 6.04%H 13.99%N Found:71.91%C 5.86%H 13.54%N

EXAMPLE 12 1,2,3,4-Tetrahydrocyclopentb!indol-3-(N,phenylmethoxy-carbonyl)amine

To a stirred solution of 1,2,3,4-tetrahydrocyclopent b!indol-3-amine (5g) in 50 ml CH₂ Cl₂ at room temperature was added triethylamine (3.2 g)followed by 5.4 grams of benzyl chloroformate in 25 ml CH₂ Cl₂. Themixture was stirred for 2 hours and thereafter washed successively withwater (50 ml), 10% HCl (50 ml) and water (50 ml). The CH₂ Cl₂ solutionwas dried (Na₂ SO₄), concentrated in vacuo and purified by flashchromatography eluting with 2:1 hexane/acetone to give 2.0 grams1,2,3,4-tetrahydrocyclopent b!indol-3-(N-phenylmethoxycarbonyl)amine.

ANALYSIS: Calculated for C₁₉ H₁₈ N₂ O₂ : 74.49%C 5.92%H 9.14%N Found:74.23%C 5.99%H 8.96%N

EXAMPLE 13 1,2,3,3a,4,8b -Hexahydrocyclopent b!indol-3-amine2-naphthalene sulfonate hemihydrate

1,2,3,4-Tetrahydrocyclopent b!indol-3-amine (2.0 g) was placed in athree-neck flask under nitrogen and 34 ml of a 1.0Mborane-tetrahydrofuran complex in tetrahydrofuran was added dropwise viaa syringe. The mixture was stirred at 0° C. for 0.5 hour and thereaftertrifluroacetic acid (34 ml) was added in a dropwise manner. Afterstirring for 2 hours, the tetrahydrofuran was removed in vacuo, and theresidue was made basic with 10% NaOH, extracted with CH₂ Cl₂ (2×75 ml)and concentrated to an oil (2 grams). A 1.0 gram sample of the oil wasdissolved in ether (200 ml) and a solution of 1.3 grams of 2-napthalenesulfonic acid in ether was added in a dropwise manner with stirring. Theprecipitate which formed was collected by filtration under nitrogen.

ANALYSIS: Calculated for C₁₁ H₁₅ N₂.C₁₀ H₈ SO₃.0.5H₂ O: 64.41%C 5.93%H7.15%N Found: 64.34%C 5.33%H 6.73%N

EXAMPLE 14 1,2,3,3a,4,8b-Hexahydro-4-methylcyclopent b!indol-3-amine2-naphthalene sulfonate

4-Methyl-1,2,3,4-tetrahydrocyclopent b!indol-3-amine (10.2 g) was placedin a three-neck flask under nitrogen and 17 ml of a 1.0Mborane-tetrahydrofuran complex in tetrahydrofuran was added dropwise viaa syringe. The mixture was stirred at 0° C. for 0.5 hours and thereaftertrifluoroacetic acid (185 ml) was added via a pressure-addition funnel.After stirring for 1 hour, the tetrahydrofuran was removed in vacuo, andthe residue was basified with 10% NaOH (pH=8), extracted with CH₂ Cl₂(2×500 ml), dried over Na₂ SO₄ and concentrated to an oil (10.3 g). Thecrude material was purified by column chromatography.

A 1.7 g sample of 1,2,3,3a,4,db-hexahydro-4-methylcyclopent-b!indol-3-amine was dissolved in 150 ml Et₂ O and a solution of 1.9 g of2-naphthalene sulfonic acid in ether was added in a dropwise manner withstirring. A solid was collected by filtration under N₂.

ANALYSIS: Calculated for C₁₂ H₁₇ N₂.C₁₀ H₈ SO₃ : 66.64%C 6.10%H 7.06%NFound: 66.74%C 5.66%H 6.77%N

EXAMPLE 15 1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-3-(2-propynyl)amine hydrochloride

1,2,3,3a,4,8b-Hexahydro-4-methylcyclopent b!indol-3-amine (5.0 grams)was dissolved in 50 ml tetrahydrofuran along with triethylamine (2.7grams). The solution was cooled to 0° C. and propargyl bromide (3.2grams) in 20 ml tetrahydrofuran was added slowly. After the addition,the mixture was allowed to come up to room temperature and stirredovernight. The tetrahydrofuran was stripped off and the residue taken upin 200 ml CH₂ Cl₂. The organic layer was extracted with 10% HCl (2×70ml). The aqueous fractions were combined and basified with 10% NaOH. Theaqueous layer was extracted with 2×200 ml CH₂ Cl₂ and the organic layerswere combined and dried over sodium sulfate. The solvent was removed invacuo. Flash chromatography on silica gel gave1,2,3,3a,4,8b-hexahydro-4-methylcyclopent b!indol-3-(2-propynyl)amine(2.0 grams) as a reddish brown oil.

A 1.46 g sample of the indoline was dissolved in ether and stirredvigorously. An ethereal HCl solution was added to this solution untilneutral (pH=6). The solids were then filtered and dried under N₂ giving1,2,3,3a,4,8b-hexahydro-4-methylcyclopent b!indol-3-(2-propynyl)aminehydrochloride as a fine white powder (1.46 grams).

ANALYSIS: Calculated for C₁₅ H₁₈ N₂.HCl: 68.56%C 7.30%H 10.68%N Found:68.21%C 7.27%H 10.54%N

EXAMPLE 16 7-Chloroacetyl-1,4-dihydro-4-methylcyclopentb!indol-3(2H)-one

Aluminum chloride (8.5 g) was suspended in CH₂ Cl₂ (20 ml) at 0° C.,chloroacetyl chloride (7.2 g) was slowly added and the mixture wasstirred for 5 minutes. This mixture was added dropwise to a stirredsolution of 1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one (6.0 g) in100 ml CH₂ Cl₂ at 0° C. The mixture was stirred at 0° C. for 45 minutesand thereafter an additional equivalent of preformed solution ofaluminum chloride and chloroacetyl chloride in methylene chloride wasintroduced in a dropwise manner. After 30 minutes the reaction mixturewas slowly poured into a stirred ice/water mixture. The layers wereseparated and the CH₂ Cl₂ layer was washed with NaHCO₃, dried (Na₂ SO₄)and concentrated to an oil. Purification by flash chromatography onsilica gel eluting with hexane/acetone provided7-chloroacetyl-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one (4.5 g).

ANALYSIS: Calculated for C₁₄ H₁₂ ClNO₂ : 64.25%C 4.62%H 5.35%N Found:64.35%C 4.61%H 5.24%N

EXAMPLE 17 7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopentb!indol-3(2H)-one

To a stirred solution of 7-chloroacetyl-1,4-dihydro-4-methylcyclopentb!indol-3(2H)-one (2.0 g)in chloroform (100 ml) was added sodiumphosphate (1.02 g) followed by m-chloroperbenzoic acid (2.5 g, 50-60%purity). The mixture was stirred at room temperature under a nitrogenatmosphere for 14 hours. Saturated NaHCO₃ aqueous solution (50 ml) wasadded, the layers separated and the organic layer washed with water(2×50 ml). The solution was dried (Na₂ SO₄), filtered and concentratedto give a yellow oil which crystallized upon standing. Recrystallizationfrom with EtOH provided 7-chloroacetyloxy-1,4-dihydro-4-methylcyclopentb!indol-3(2H)-one (1.1 g).

ANALYSIS: Calculated for C₁₄ H₁₂ ClNO₃ : 60.55%C 4.36%H 5.04%N Found:60.47%C 4.33%H 4.98%N

EXAMPLE 18 1,4,-Dihydro-7-methylaminocarbonyloxy-4-methylcyclopent-b!indol-3(2H),one

7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one (5.0g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50ml) was added and the mixture was stirred at room temperature for 3hours. The mixture was concentrated in vacuo, CH₂ Cl₂ (100 ml) was addedfollowed by 10% HCl until the aqueous layer was neutralized. The layerswere separated and the aqueous phase extracted with CH₂ Cl₂ (2×100 ml).The organic portion was dried (Na₂ SO₄) and concentrated and the residuewas recrystallized from 95% EtOH to provide1,4-dihydro-7-hydroxy-4-methylcyclopent b!indol-3(2H)-one as anoff-white solid. The phenol was dissolved in CH₂ Cl₂ (100 ml), andthereafter 1,8-diazabicyclo 5.4.0!undec-7-ene (0.4 g) was added followedby methyl isocyanate (1.4 g) and the mixture was stirred overnight. Themixture was concentrated in vacuo to afford an oily solid which wascrystallized from EtOH to provide1,4-dihydro-7-methylaminocarbonyloxy-4-methyl-cyclopentb!indol-3(2H)-one (1.1 g).

ANALYSIS: Calculated for C₁₄ H₁₄ N₂ O₃ : 65.11%C 5.46%H 10.85%N Found:65.20%C 5.32%H 10.74%N

EXAMPLE 19 3-Acetyloxyimino-4-methyl-1,2,3,4-tetrahydrocyclopentb!-indol-7-yl acetate

7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one (8.0g) was suspended in EtOH (200 ml) and a solution of NaOAc (15.6 g) inwater (25 ml) and a solution of hydroxylamine hydrochloride (8.0 g) inwater (25 ml) were added and the mixture was refluxed for 3 hours. Themixture was concentrated in vacuo and the residue was recrystallizedfrom 95% EtOH to provide3-hydroxyamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol as anoff-white solid. The oxime was dissolved in tetrahydrofuran (100 ml),and thereafter acetic anhydride (8.1 g) and 4-dimethylaminopyridine (400mg) were added and the mixture was stirred under nitrogen at ambienttemperature overnight. The mixture was concentrated in vacuo, CH₂ Cl₂(100 ml) was added and the solution was washed successively with water(50 ml), 5% NaHCO₃ (50 ml) and water (50 ml). After drying (Na2SO4), thesolvent was removed in vacuo and the product recrystallized from EtOH toprovide 3-acetyloximino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl acetate (1.7 g).

ANALYSIS: Calculated for C₁₆ H₁₆ N₂ O₂ : 63.99%C 5.37%H 9.33%N Found:63.56%C 5.37%H 9.29%N

EXAMPLE 20 4-Methyl-3-phenylmethylamino-1,2,3,4-tetrahydrocyclopent-b!indol-7-ol

To a stirred suspension of7-chloroacetyloxy-1,4-dihydro-4-methyl-cyclopent b!-indol-3(2H)-one (6.0g) in toluene (50 ml) was added benzylamine (9.2 g) and the mixture washeated at reflux temperature with azeotropic removal of water using aDean Stark trap. After 4 hours, TLC analysis indicated completeconversion to product. The mixture was allowed to cool to roomtemperature and filtered, and the solid material was washed withacetonitrile. The filtrate and washings were combined, concentrated andpurified by flash chromatography on silica gel (2:1 hexane/acetone aseluent). The crystals which formed in the product-containing fractionswere collected via filtration to give4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(11 grams) and the filtrate was concentrated to give an oil (3.0 grams)which crystallized upon standing.

ANALYSIS: Calculated for C₁₉ H₁₈ N₂ O: 78.59%C 6.25%H 9.65%N Found:78.62%C 6.21%H

EXAMPLE 21 4-Methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent-b!indol-7-ol

To a stirred solution prepared from4-methyl-3-phenylmethylamino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(16.0 g), isopropanol (200 ml) and methanol (50 ml) was added sodiumborohydride (4.8 g) and the mixture was stirred under nitrogen atambient temperature for 3 hours. The mixture was cooled to 0° C., waterwas slowly added and the mixture was stirred 0.5 hour. The mixture wasextracted with CH₂ Cl₂ (2×200 ml), and the CH₂ Cl₂ extracts were dried(Na₂ SO₄), concentrated and chromatographed on silica gel eluting with2:1 hexanes/acetone. The product-containing fractions were combined togive 4.25 grams of4-methyl-3-(phenylmethylamino)-1,2,3,4-tetrahydrocyclopent b!indol-7-ol.

ANALYSIS: Calculated for C₁₉ H₂₀ N₂ O: 78.05%C 6.89%H 9.58%N Found:78.20%C 6.97%H 9.54%N

EXAMPLE 22 4-Methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent-b!indol-7-yl methylcarbamate

To a stirred solution of4-methyl-3-phenylmethylamino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(2.0 g) in CH₂ Cl₂ (40 ml) was added 1,8-diazabicyclo 5.4.0!undec-7-ene(0.16 g) followed by the dropwise addition of methyl isocyanate (0.39 g)in CH₂ Cl₂ (10 ml). The reaction was monitored via TLC and after 3 hoursthe solution was concentrated and the precipitate was collected andrecrystallized from acetonitrile to give4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate (1.85 grams).

ANALYSIS: Calculated for C₂₁ H₂₁ N₃ O₂ : 72.60%C 6.09%H 12.09%N Found:72.59%C 6.01%H 12.05%N

EXAMPLE 23 4-Methyl-3-phenylmethylamino-1,2,3,4-tetrahydrocyclopent-b!indol-7-yl methylcarbamate maleate

To a stirred solution of4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate (1.8 g) in acetic acid (25 ml) was added sodiumcyanoborohydride (0.8 g). The reaction was monitored via TLC and after 2hours CH₂ Cl₂ (50 ml) was added and the solution was washed withsaturated NaHCO₃ until neutral. The CH₂ Cl₂ layer was dried (Na₂ SO₄),filtered and concentrated to give an oil which was purified via flashchromatography, eluting with 2:1 hexane/acetone. The product-containingfractions were collected and concentrated to an oil which was dissolvedin ether and thereafter an ethereal maleic acid solution was added untilthe mixture became acidic. The maleate salt of4-methyl-3-phenylmethylamino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate (0.8 g) which precipitated as a colorless solid wascollected.

ANALYSIS: Calculated for C₂₁ H₂₁ N₃ O₂.C₄ H₄ O₄ : 64.51%C 5.85%H 9.03%NFound: 64.13% 5.75%H 8.97%N

EXAMPLE 24 4-Methyl-3-(2-phenylcyclopropyl)imino!-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate

To a stirred suspension of 1,4-dihydro-7-hydroxy-4-methylcyclopentb!indol-3(2H)-one (5.0 g) in acetonitrile (100 ml) was addedphenylcyclopropylamine hydrochloride (4.2 g) followed by triethylamine(2.5 g). The solution was stirred at room temperature under a nitrogenatmosphere while titanium (IV) isopropoxide was added in a dropwisemanner. The mixture was stirred for 3 hours and thereafter quenched withice/water. The mixture was filtered, the solids were washed with CH₂Cl₂, the layers were separated and the organic portion was dried (Na₂SO₄). After concentration, the crude product was purified via flashchromatography eluting with hexane/acetone (2:1) to give 4-methyl-3-(2-phenylcyclopropyl)imino!1-1,2,3,4-tetrahydrocyclopent b!indol-7-ol.

To a stirred solution of this product (1.0 g) in CH₂ Cl₂ (9.0 ml) wasadded 1,8-diazabicyclo 5.4.0!undec-7-ene (68 mg) followed by thedropwise addition of methyl isocyanate (0.18 g) in CH₂ Cl₂ (1.0 ml). Thereaction was monitored via TLC and after 0.5 hour the solution wasconcentrated and the precipitate was collected and recrystallized twicefrom acetonitrile to give 4-methyl-3-(2-phenylcyclopropyl)imino!-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate (0.55 gram).

ANALYSIS: Calculated for C₂₁ H₂₁ N₃ O₂ : 73.97%C 6.21%H 11.25%N Found:73.57%C 6.25%H 11.13%N

EXAMPLE 25 3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent-b!indol-7-ol

7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one (15.0g) and cyclopropylamine (9.6 g) were dissolved in 300 ml toluene andcooled to -10° C. Titanium tetrachloride (6.3 g) dissolved in 50 mltoluene was added slowly to the first solution. The reaction mixture wasallowed to come up to room temperature and stirred overnight. The nextday another 1.5 equivalents of the amine (4.6 g) was added to thereaction mixture and the mixture was stirred for one hour. The reactionmixture was filtered through a pad of silica gel, eluting with 3:1hexane/ethyl acetate, giving a yellow oil after removal of solvents.3-Cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!-indol-7-olwas isolated as a light yellow solid (3.3 g) after flash chromatographyand recrystallization from ethyl acetate.

ANALYSIS: Calculated for C₁₅ H₁₆ N₂ O: 74.97%C 6.71%H 11.66%N Found:74.57%C 6.54%H 11.37%N

EXAMPLE 26 3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-ol maleate

3-Cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(17.3 g) was dissolved in 5:1 isopropanol/methanol (250 ml), under N₂and stirred at room temperature. Sodium borohydride (8.2 g) was addedand the reaction mixture was stirred overnight. Thin layer analysisindicated a complete reaction. The solution was cooled to 0° C. andwater (100 ml) was added slowly. Ethyl acetate (250 ml) was added and,after separating the layers, the organic portion was washed successivelywith brine (2×100 ml), and water (2×100 ml) and dried over Na₂ SO₄, andthereafter the solvent was removed in vacuo. The crude material waspurified by preparative HPLC using a 2:1 hexane/ethyl acetate solventsystem. The free base was isolated as light brown/yellow oil (7.8 g). Astirred solution of the free base (0.6 g) in ether (200 ml) was treatedslowly with a solution prepared from 0.3 g maleic acid, 50 ml Et₂ O and5 ml EtOH. 3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-ol maleate was isolated as a light yellow solid (0.8 g) afterfiltering and drying under N₂.

ANALYSIS: Calculated for C₁₅ H₁₈ N₂ O.C₄ H₄ O₄ : 63.68%C 6.19%H 7.82%NFound: 63.47%C 6.31%H 7.69%N

EXAMPLE 27 3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl phenylmethylcarbonate

3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!-indol-7-ol (5.5 g) was dissolved in 250 ml CH₂ Cl₂ along withtriethylamine (2.8 g) and cooled to 0° C. while stirring. Benzylchloroformate (3.9 g) dissolved in 50 ml CH₂ Cl₂ was added slowly to thefirst solution. After complete addition, the reaction mixture wasallowed to come to room temperature, washed with H₂ O(2×150 ml) anddried over Na₂ SO₄, and the solvent was removed in vacuo. The crudematerial was purified by flash column chromatography using EtOAc as thesolvent. 3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl phenylmethylcarbonate was isolated as a yellow brown foam(4.1 g).

ANALYSIS: Calculated for C₂₃ H₂₄ N₂ O₃ : 73.38%C 6.43%H 7.44%N Found:73.41%C 6.80%H 7.48%N

EXAMPLE 283-(N-Cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-ol

3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(8.7 g) was placed in a 3-neck flask and cooled to 0° C. in an ice-waterbath. A 1M solution of borane in THF (540 ml) was added in a dropwisemanner. The mixture was stirred for 1 hour while it was slowly warmed toroom temperature. The mixture was cooled back down to 0° C. andtrifluoroacetic acid (119 ml) was added in a dropwise manner. Thesolution was stirred for 15 minutes and THF was removed in vacuo. Themixture was neutralized with 10% NaOH solution, extracted with methylenechloride (4×500 ml), dried (Na₂ SO₄) and concentrated to give3-(N-cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-ol (8.8 g).

EXAMPLE 293-(N-Cyclopropyl)-N-methylaminocarbonyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-ol hydrochloride

3-(N-Cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-ol (8.8 g) was dissolved in CH₂ Cl₂ (400 ml) along withtriethylamine (4.4 g). The solution was cooled to 0° C. and stirredunder N₂. Benzyl chloroformate (6.1 g) dissolved in CH₂ Cl₂ (50 ml) wasadded slowly to the first solution. The reaction was monitored by thinlayer chromatography while adding an additional equivalent (6.1 g) ofthe chloroformate until the reaction was complete. The solution waswarmed to room temperature before washing with water (2×100 ml), dryingover Na₂ SO₄ and concentrating to an oil, which was purified bypreparative HPLC using 3:1 hexane/acetone as the solvent system.3-(N-Cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-yl phenylmethylcarbonate was isolated (7.0 g), which wascharacterized by NMR, MS and IR. This material was dissolved in CH₂ Cl₂(250 ml) and the solution treated with 1,8-diazabicyclo5.4.0!undec-7-ene (DBU; 0.4 g). The mixture was cooled to 0° C. andstirred while a solution of methyl isocyanate (1.1 g) in 50 ml CH₂ Cl₂was added slowly. The reaction was monitored by TLC (1:1 hexane/acetone)while adding another 2.5 equivalents (2.7 g) of methyl isocyanate untilthe reaction was complete. The solution was warmed to room temperature,washed successively with brine (2×100 ml) and water (1×100 ml), driedover Na₂ SO₄ and concentrated. The oil was purified by flash columnchromatography using ethyl acetate as the solvent system.3-(N-Cyclopropyl-N-methylaminocarbonyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-yl phenylmethylcarbonate was isolated (4.5 g). The materialwas dissolved in absolute ethanol (190 ml), and 10% palladium on carbon(10% by weight; 0.4 g) was added. The solution was placed in a Parrshaker bottle, charged with H₂ (45 psi) and shaken for 2 hours. Thecatalyst was filtered and the filtrate was concentrated. The oil wastriturated with EtOAc (50 ml) and CH₂ Cl₂ (5 ml) to give an off-whitesolid (1.05 g).

3-(N-Cyclopropyl-N-methylaminocarbonyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent b!indol-7-ol was characterized by NMR,MS and IR. The solid (0.8 g) was dissolved in 8:1 Et₂ O/EtOH (200 ml)initially and ethereal hydrogen chloride was added slowly until thesolution became neutral and then more Et₂ O (800 ml) was added.

3-(N-Cyclopropyl-N-methylaminocarbonyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!indol-7-ol hydrochloride was isolated as an off-white solid afterfiltering and drying under N₂ (0.65 g).

ANALYSIS: Calculated for C₁₇ H₂₃ N₂ O₃.HCl: 60.44%C 7.16%H 12.44%NFound: 60.77%C 7.41%H 12.67%N

EXAMPLE 30 3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate

3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(2.2 g) was dissolved in CH₂ Cl₂ (200 ml) with 1,8-diazabicyclo5.4.0!undec-7-ene (DBU; 0.21 g) and the solution was cooled to 0° C. Asolution of methyl isocyanate (0.52 g in 30 ml CH₂ Cl₂) was added slowlyto the cooled solution and the reaction was monitored by thin layerchromatography (silica gel, 1:1 hexane/ethyl acetate). After warming toroom temperature, the mixture was washed successively with water (2×100ml), brine (1×100 ml) and again with water (1×100 ml). The organic layerwas dried over Na₂ SO₄ and the solvent removed in vacuo. The crudematerial was recrystallized from acetonitrile.3-(N-Cyclo-propyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate was isolated as light yellow/white plates(1.0 g).

ANALYSIS: Calculated for C₁₇ H₂₁ N₃ O₂ : 68.21%C 7.07%H 14.04%N Found:68.08%C 6.57%H 13.97%N

EXAMPLE311,2,3,3a,4,8,b-Hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminocarbonyl)aminocyclopentb!indol-7-yl phenylmethylcarbonate

To a stirred solution of1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethylaminocyclopentb!indol-7-ol (12.0 g) in CH₂ Cl₂ (125 ml) was added triethylamine (4.08g). The mixture was cooled to 0° C. and a solution of benzylchloroformate (6.8 g) in CH₂ Cl₂ (50 ml) was added slowly in a dropwisemanner. After three hours the reaction mixture was washed with water(2×100 ml), dried over Na₂ SO₄ and concentrated to give 17.0 grams of anoil. The crude4-methyl-3-(N-phenylmethyl)amino-1,2,3,3a,4,8b-hexahydrocyclopentb!indol-7-yl phenylmethylcarbonate (17.0 g) was dissolved in CH₂ Cl₂(125 ml) and 1,8-diazabicyclo 5.4.0!undec-7-ene (0.9 g) was addedfollowed by the dropwise addition of a solution of methyl isocyanate(2.6 g) in CH₂ Cl₂ (25 ml). The reaction mixture was stirred for 2 hoursand an additional 0.5 gram of methyl isocyanate was added. The reactionmixture was stirred for an additional 15 minutes and thereafterconcentrated in vacuo to give an oil which was purified by flashchromatography on silica gel eluting with 2:1 hexane/ethyl acetate. Theproduct-containing fractions were collected and concentrated to give anoil (5.5 g).

ANALYSIS: Calculated for C₂₂ H₂₅ N₃ O₄ : 71.73%C 6.43%H 8.65%N Found:71.67%C 6.59%H 8.67%N

EXAMPLE 321,2,3,3a,4,8,b-Hexahydro-4-methyl-3-phenylmethoxycarbonyl-aminocyclopentb!indol-7-ol

A solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopentb!indol-7-ol (14.0 g) was placed in a 3-neck flask and cooled to 0° C.in an ice-water bath. A solution of 1M borane/THF in THF (145 ml) wasadded in a dropwise manner. The mixture was stirred for 1 hour while itwas slowly warmed to room temperature. The mixture was cooled back to 0°C. and trifluoroacetic acid was added in a dropwise manner. The solutionwas stirred for 15 minutes, neutralized with 10% NaOH (Aq), extractedwith CH₂ Cl₂, dried (Na₂ SO₄) and concentrated to give1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethylaminocyclopentb!indol-7-ol (14 grams).

20% Palladium hydroxide on carbon (1.4 g) was added to a solution of1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethylaminocyclopentb!-indol-7-ol (14 grams) in ethanol (100 ml) and the mixture washydrogenated at 45 psi H₂ pressure using a Parr apparatus at 50° C. for5 hours. The mixture was filtered and the solution was concentrated togive 3-amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent b!indol-7-ol(10.7 grams).

To a solution of 3-amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopentb!-indol-7-ol (10.7 grams) in methylene chloride (125 ml) was addedtriethylamine (5.6 grams) followed by the dropwise addition of benzylchloroformate (10.0 grams) in methylene chloride (25 ml). The mixturewas stirred for 2 hours, extracted with water, dried (Na₂ SO₄) andconcentrated. The product was purified by chromatography on silica gel,eluting with 2:1 hexane/acetone to provide1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethoxycarbonylaminocyclopentb!indol-7-ol.

EXAMPLE 331,2,3,3a,4,8,b-Hexahydro-4-methyl-3-(N-phenylmethoxycarbonyl)aminocyclopentb!indol-7-yl methylcarbamate

To a stirred solution of1,2,3,3a,4,8b-hexahydro-4-methyl-3-(N-phenylmethoxycarbonyl)aminocyclopentb!indol-7-ol (1.8 g) in CH₂ Cl₂ (75 ml) was added 1,8-diazabicyclo5.4.0!undec-7-ene (0.12 g) followed by the dropwise addition of asolution of methyl isocyanate (0.36 g) in CH₂ Cl₂ (25 ml). The reactionmixture was stirred for 2 hours and an additional 0.1 gram of methylisocyanate was added. The reaction mixture was stirred for an additional15 minutes and concentrated in vacuo to give an oil which was purifiedby flash chromatography on silica gel eluting with 2:1 hexane/ethylacetate. The product which crystallized from the pure fractions wascollected by filtration to give 600 mg and the filtrate was concentratedto give an oil (800 mg) which crystallized upon standing.

ANALYSIS: Calculated for C₂₂ H₂₅ N₃ O₄ : 66.82%C 6.37%H 10.63%N Found:66.91%C 6.47%H 10.66%N

EXAMPLE 343-Methylaminocarbonyloximino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate hemihydrate

To a stirred suspension of3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol (3.0 g)in CH₂ Cl₂ (100 ml) was added 1,8-diazabicyclo 5.4.0!undec-7-ene (630mg) followed by methyl isocyanate (1.9 g) and the mixture was stirredovernight at ambient temperature. The mixture was concentrated in vacuoand the resulting solid was recrystallized from ethanol to give3-methylaminocarbonyloximino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate hemihydrate (1.7 g).

ANALYSIS: Calculated for C₁₆ H₁₈ N₄ O₄. 0.5H₂ O: 56.68%C 5.66%H 16.53%NFound: 56.57%C 5.46%H 16.68%N

EXAMPLE 351,2,3,3,a,4,8b-Hexahydro-4-methyl-3-methylaminocarbonylaminocyclopentb!indol-7-ol hydrochloride monohydrate

A solution of1,2,3,3a,4,8b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminocarbonyl)aminocyclopentb!indol-7-yl phenylmethyl carbonate (1.7 g) in glacial acetic acid (100ml) was hydrogenated at 45 psi H₂ and 50° C. in the presence of 20% Pdhydroxide on carbon utilizing a Parr apparatus. After four hours, TLCindicated a complete reaction with the formation of a major product aswell as a side product. The Pd catalyst was filtered under nitrogen andthe filtrate concentrated in vacuo. The material was chromatographed onsilica gel eluting with 10% MeOH/CH₂ Cl₂. The product-containingfractions were collected and concentrated. The resulting oil wasdissolved in EtOH (25 ml) and Et₂ O (150 ml), the solution was filtered,and ethereal HCl was added to the filtrate until the solution becameacidic. The colorless solid which formed was collected under N₂ anddried under vacuum to give1,2,3,3a,4,8b-hexahydro-4-methyl-3-methylaminocarbonylaminocyclopentb!indol-7-ol hydrochloride monohydrate (0.25 g).

ANALYSIS: Calculated for C₁₄ H₁₉ N₃ O₂.HCl.H₂ O: 53.25%C 7.02%H 13.31%NFound: 53.26%C 6.54%H 12.78%N

EXAMPLE 361,2,3,3a,4,8b-Hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminocarbonyl)aminocyclopentb!indol-7-ol hydrochloride

A solution of1,2,3,3a,4,8b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminocarbonyl)aminocyclopentb!indol-7-yl phenylmethyl carbonate (2.0 g) in absolute ethanol (100 ml)was hydrogenated at 45 psi H₂ in the presence of 5% Pd-carbon utilizinga Parr apparatus. After two hours, TLC indicated a complete reactionwith the formation of a single product. The Pd catalyst was filteredunder nitrogen and the filtrate concentrated in vacuo. The resulting oilwas dissolved in EtOAc (25 ml) and Et₂ O (150 ml), the solution wasfiltered and ethereal HCl was added to the filtrate until the solutionbecame acidic. The colorless solid which formed was collected under N₂and dried overnight at 40° C. under vacuum to give1,2,3,3a,4,8b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminocarbonyl)aminocyclopentb!indol-7-ol hydrochloride (1.4 g).

ANALYSIS: Calculated for C₂₁ H₂₅ N₃ O₂.HCl: 65.02%C 6.76%H 10.83%NFound: 64.95%C 6.85%H 10.84%N

EXAMPLE 37 4-Methyl-3-phenylethylimino-1,2,3,4-tetrahydrocyclopentb!indol-7-ol hemihydrate

To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydrocyclopentb!-3-one (5.0 g) in acetonitrile (100 ml) were added phenethylamine (6.0g) and titanium isopropoxide (14.1 g), and the resulting mixture wasstirred under nitrogen at ambient temperature for 3 hours. The mixturewas poured onto ice/water (200 ml) and thereafter, CH₂ Cl₂ (500 ml) wasadded. The mixture was filtered, and the organic layer was separatedfrom the filtrate, dried over sodium sulfate and concentrated in vacuo.Crystallization from CH₂ Cl₂ /hexane provided4-methyl-3-phenylethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-olhemihydrate (3.0 g).

ANALYSIS: Calculated for :C₂₀ H₂₀ N₂ O 1/2H₂ O 76.65%C 6.75%H 8.94%NFound: 76.53%C 6.38%H 8.89%N

EXAMPLE 38 4-Methyl-3-phenylethylimino-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate

To a stirred solution of4-methyl-3-phenylethylimino-1,2,3,4-tetrahydrocyclopent- b!indol-7-olhemihydrate (1.43 g) in CH₂ Cl₂ (25 ml) was added 1,8-diazabicyclo5.4.0!undec-7-ene (0.11 g). Methylisocyanate (0.27) in CH₂ Cl₂ (20 mlwas added to the reaction mixture. The reaction was monitored by TLC andafter 3 hours the CH₂ Cl₂ was evaporated off. The brown residue wasrecrystallized from acetonitrile.

ANALYSIS: Calculated for :C₂₂ H₂₃ N₃ O₂ 73.11%C 6.41%H 11.63%N Found73.03%C 6.35%H 11.65%N

EXAMPLE39 4-Methyl-3-(2-phenylethyl)amino-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate hydrochloride hemihydrate

To a stirred solution of4-methyl-3-(2-phenylethyl)imino-1,2,3,4-tetrahydrocyclopentb!indol-7-ylmethylcarbamate (0.80 g) in acetic acid (8 ml), ethanol (8ml), isopropanol (8 ml) and tetrahydrofuran (8 ml) was added sodiumcyanoborohydride (0.35 g) under nitrogen. The reaction was monitored byTLC and after 1 hour the solution was neutralized with saturated NaHCO₃,extracted with EtOAc, dried over Na₂ SO₄, and concentrated in vacuo. Theresulting yellow oil was dissolved in a minimum amount of EtOAc, dilutedwith ether and thereafter, an etheral HCl solution was added. Theresulting white solid was collected via filtration. Crystallization fromethanol afforded4-methyl-3-(2-phenylethyl)amino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethyl carbamate hydrochloride hemihydrate (0.68 g). The reaction wasrepeated and the material combined.

ANALYSIS: Calculated for C₂₂ H₂₅ N₃ O₂.HCl.1/2H₂ O: 64.62%C 6.65%H10.28%N Found: 64.56%C 6.72%H 9.91%N

EXAMPLE 40 4-Methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopentb!-indol-7-yl methylcarbamate

To a stirred suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopentb!indol-3(2H)-one (5.5 g) in acetonitrile (100 ml) was added propargylamine (3.0 g), the solution was stirred at room temperature under anitrogen atmosphere while titanium (IV) isopropoxide (15.6 g) was addedin a dropwise manner. The mixture was stirred for 16 hours beforequenching with ice water. The mixture was filtered, the solids werewashed with CH₂ Cl₂, the layers were separated and the organic portionwas dried (Na₂ SO₄). After concentration, the crude product was purifiedvia flash chromatography eluting with hexane/acetone (2:1) to give4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol.

To a stirred solution of4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(3.4 g) in CH₂ Cl₂ (15.0 ml) was added 1,8-diazabicyclo5.4.0!undec-7-ene (326 mg) followed by the dropwise addition of methylisocyanate (0.8 g) in CH₂ Cl₂ (5.0 ml). The reaction was monitored viaTLC and after 1.0 hour, the solution was concentrated and the crudeproduct was purified via flash chromatography eluting withhexane/acetone (2:1). The product which precipitated out of the purefractions was collected to give4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate (1.2 grams) and the fractions were concentrated to givean additional 0.9 gram.

ANALYSIS: Calculated for C₁₇ H₁₇ N₃ O₂ : 69.14%C 5.80%H 14.23%N Found:68.94%C 5.81%H 13.94%N

EXAMPLE41 4-Methyl-3-(2-propynyl)amino-1,2,3,4-tetrahydrocyclopentb!-indol-7-yl methylcarbamate hydrochloride monohydrate

To a stirred solution of4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate (1:1 g) in acetic acid (10 ml) was added sodiumcyanoborohydride (0.57 g). The reaction was monitored via TLC and after2 hours, methylene chloride (50 ml) was added and the solution waswashed with saturated NaHCO₃ until neutral. The methylene chloride layerwas dried (Na₂ SO₄), filtered and concentrated. The resulting materialwas chromatographed on silica gel, eluting with 2:1 hexane/acetone andthe pure fractions were collected and concentrated. The resulting solidwas dissolved in a minimum amount of EtOAc, diluted with ether andthereafter, ethereal HCl solution was added. The resulting solid wascollected via filtration under nitrogen to give4-methyl-3-(2-propynyl)amino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate hydrochloride monohydrate (0.4 grams). The reaction wasrepeated and the products were combined.

ANALYSIS: Calculated for C₁₇ H₁₉ N₃ O₂.HCl.H₂ O: 58.04%C 6.30%H 11.94%NFound: 57.99%C 6.03%H 11.82%N

EXAMPLE42 4-Methyl-3-(2-phenylethyl)amino-1,2,3,4-tetrahydrocyclopentb!-indol-7-yl phenylmethylcarbamate hydrochloride hemihydrate

To a stirred solution of4-methyl-3-(2-phenylethyl)imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol(2.70 g) in CH₂ Cl₂ (100 ml) was added 1,8-diazabicyclo 5.4.0!undecene(0.21 g). Benzyl isocyanate (0.83 g) was added to the reaction mixturevia a syringe and the mixture stirred under nitrogen. Additional benzylisocyanate was added after 120 and 180 minutes in 1/4 and 1/2equivalents, respectively. The reaction was monitored by TLC and after185 minutes the solution was concentrated in vacuo. The crude reactionresidue (2.72 g) showed carbamate formation according to proton NMR andMS. The residue was dissolved in glacial acetic acid (75 ml) withstirring under nitrogen. A yellow precipitate formed upon addition ofsodium cyanoborohydride (0.98g) and dissolved after 30 minutes. Oneequivalent of sodium cyanoborohydride was added after 3 hours. After 30minutes, TLC showed complete reaction. The reaction mixture wasneutralized with saturated sodium bicarbonate solution, extracted withethyl acetate, dried over Na₂ SO₄, and concentrated in vacuo. The freebase was dissolved in ether and an ethereal solution of HCl was added.The resulting white solid was collected via filtration.

ANALYSIS: Calculated for C₂₈ H₃₀ N₃ O₂.HCl.1/2H₂ O: 69.34%C 6.44%H8.66%N Found: 69.45%C 6.30%H 8.72%N

EXAMPLE43 4--Methyl-3-2-(4-morpholinyl)ethyl!imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol

To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydrocyclopentb!indol-3-one (8.00 g) in acetonitrile (125 ml) under nitrogen wereadded 4-(2-aminoethyl)morpholine (10.35 g) and titanium isopropoxide(22.60 g). The reaction was monitored by TLC and after two hoursadditional equivalents of 4-(2-aminoethyl)morpholine (5.17 g) andtitanium isopropoxide (11.30 g) were added. Fourteen hours later thereaction was quenched with water (200 ml). EtOAc (200 ml) was added andthe mixture stirred for fifteen minutes and filtered. The layers wereseparated, the aqueous layer was extracted with ethyl acetate, and thecombined organics were dried (Na₂ SO₄) and concentrated in vacuo. Theresulting yellow solid was dried yielding 6.65 g. of product. A 2 gsample of the solid was further purified by crystallization from CH₂ Cl₂/hexane to afford 1.2 g of 4-methyl-3-2-(4-morpholinyl)ethyl!imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol.

ANALYSIS: Calculated for C₁₈ H₂₃ N₃ O₂ : 68.98%C 7.40%H 13.41%N Found:68.78%C 7.52%H 13.26%N

We claim:
 1. A compound of the formula ##STR40## where n is 2, 3, 4 or5; X is hydrogen, loweralkyl, loweralkoxy, hydroxy, halogen,trifluoromethyl or nitro; R₃ is hydrogen, lower alkyl, aryl lower alkyl,lower alkyl carbonyl or lower alkoxy carbonyl; R₄ is --OH, ##STR41##wherein R₅ is loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl,cycloalkylloweralkyl, aryl, arylloweralkyl or arylcycloalkyl; and R₆ ishydrogen, loweralkyl, aryl or arylloweralkyl; or alternatively the group##STR42## and R₇ is loweralkyl, aryl or arylloweralkyl; and R₈ ishydroxy, loweralkoxy, aminoloweralkoxy, loweralkyl, cycloalkyl,cycloalkenyl, arylloweralkyl, arylcycloalkyl, loweralkylcarbonyloxy orloweralkylaminocarbonyloxy; or a pharmaceutically acceptable additionsalt thereof.
 2. The compound as defined in claim 1, which is3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol.
 3. Thecompound as defined in claim 1, which is4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol.4. The compound as defined in claim 1, which is4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate.
 5. The compound as defined in claim 1, which is4-methyl-3- (2-phenylcyclopropyl)imino!-1,2,3,4-tetrahydrocyclopentb!indol-7-ol.
 6. The compound as defined in claim 1, which is4-methyl-3-(2-phenylcyclopropyl)imino-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate.
 7. The compound as defined in claim 1,which is 3-cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-ol.
 8. The compound as defined in claim 1, which is3-methylaminocarbonyloximino-4-methyl-1,2,3,4-tetrahydrocyclopentb!indol-7-yl methylcarbamate.
 9. The compound as defined in claim 1,which is 4-methyl-3-phenethylimino-1,2,3,4-tetrahydrocyclopentb!indol-7-ol.
 10. The compound as defined in claim 1, which is4-methyl-3-phenethylimino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylmethylcarbamate.
 11. The compound as defined in claim 1, which is4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ol.12. The compound as defined in claim 1, which is4-methyl-3-(2-phenylethyl)imino-1,2,3,4-tetrahydrocyclopent b!indol-7-ylphenylmethylcarbamate.
 13. A pharmaceutical composition comprising acompound as defined in claim 1 in an amount effective for alleviating amemory dysfunction characterized by a cholinergic deficit or foralleviating depression and a suitable carrier therefor.
 14. A method oftreating a patient in need of relief from a memory dysfunctioncharacterized by a cholinergic deficit, which comprises administering tosuch a patient an effective amount of a compound as defined in claim 1.15. A method of treating a patient in need of relief from depressionwhich comprises administering to such a patient an effective amount of acompound as defined in claim 1.